Influence of peptidase inhibitors on the apparent agonist potency of delta selective opioid peptides in vitro

Thomas H. Kramer, Geza Toth, Ronald C. Haaseth, Terry O. Matsunaga, Peg Davis, Victor J. Hruby, Thomas F. Burks

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Several peptides of diverse structure, reported to possess high affinity and selectivity for the δ opioid receptor, were studied using the mouse isolated vas deferens preparation to determine the effect of peptidase inhibition on their apparent potency. The peptides evaluated included [Leu5]enkephalin, the cyclic enkephalin analogs [D-Pen2, D-Pen5] enkephalin (DPDPE) and [D-Pen2, p-F-Phe4, D-Pen5]enkephalin (F-DPDPE), the linear enkephalin analogs [D-Ala2, D-Leu5]enkephalin (DADLE) and [D-Ser2(O-tBu), Leu5, Thr6]enkephalin (DSTBULET), and the naturally occurring amphibian peptides Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (dermenkephalin), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (deltorphin II). Concentration-response curves were determined for each peptide in the absence and presence of a combination of the peptidase-inhibiting agents bacitracin, bestatin, and captopril. A wide range of potencies was observed, both in the control state and in the presence of peptidase inhibition. The synthetic enkephalin analogs demonstrated small increases in potency with peptidase inhibition (no increase in the case of DPDPE), whereas the naturally occurring peptides were markedly increased in potency, up to as much as 123-fold for dermenkephalin. In the presence of peptidase inhibition, deltorphin II was the most potent peptide tested (IC50 = 1.13 X 10-10 molar), and as such is the most potent delta opioid agonist reported to date. Stability to metabolism must be considered in the design and evaluation of in vitro experiments using peptides of this type.

Original languageEnglish (US)
Pages (from-to)881-886
Number of pages6
JournalLife Sciences
Issue number9
StatePublished - 1991

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • Pharmacology, Toxicology and Pharmaceutics(all)


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